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| 3. |
- Saliba-Gustafsson, P., et al.
(author)
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Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy
- 2019
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 660-675
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Journal article (peer-reviewed)abstract
- Background Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. Objective We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. Methods A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. Results The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. Conclusions For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.
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- Ahl, Matilda, et al.
(author)
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Immune response in blood before and after epileptic and psychogenic non-epileptic seizures
- 2023
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In: Heliyon. - : Elsevier. - 2405-8440. ; 9:3
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Journal article (peer-reviewed)abstract
- Inflammatory processes may provoke epileptic seizures and seizures may promote an immune reaction. Hence, the systemic immune reaction is a tempting diagnostic and prognostic marker in epilepsy. We explored the immune response before and after epileptic and psychogenic non-epileptic seizures (PNES). Serum samples collected from patients with videoEEG-verified temporal or frontal lobe epilepsy (TLE or FLE) or TLE + PNES showed increased interleukin-6 (IL-6) levels in between seizures (interictally), compared to controls. Patients with PNES had no increase in IL-6. The IL-6 levels increased transiently even further within hours after a seizure (postictally) in TLE but not in FLE patients. The postictal to interictal ratio of additionally five immune factors were also increased in TLE patients only. We conclude that immune factors have the potential to be future biomarkers for epileptic seizures and that the heterogeneity among different epileptic and non-epileptic seizures may be disclosed in peripheral blood sampling independent of co-morbidities.
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| 7. |
- Ahl, Matilda, et al.
(author)
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Immune response in the eye following epileptic seizures
- 2016
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In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 13:1
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Journal article (peer-reviewed)abstract
- Background: Epileptic seizures are associated with an immune response in the brain. However, it is not known whether it can extend to remote areas of the brain, such as the eyes. Hence, we investigated whether epileptic seizures induce inflammation in the retina. Methods: Adult rats underwent electrically induced temporal status epilepticus, and the eyes were studied 6 h, 1, and 7 weeks later with biochemical and immunohistochemical analyses. An additional group of animals received CX3CR1 antibody intracerebroventricularly for 6 weeks after status epilepticus. Results: Biochemical analyses and immunohistochemistry revealed no increased cell death and unaltered expression of several immune-related cytokines and chemokines as well as no microglial activation, 6 h post-status epilepticus compared to non-stimulated controls. At 1 week, again, retinal cytoarchitecture appeared normal and there was no cell death or micro- or macroglial reaction, apart from a small decrease in interleukin-10. However, at 7 weeks, even if the cytoarchitecture remained normal and no ongoing cell death was detected, the numbers of microglia were increased ipsi- and contralateral to the epileptic focus. The microglia remained within the synaptic layers but often in clusters and with more processes extending into the outer nuclear layer. Morphological analyses revealed a decrease in surveying and an increase in activated microglia. In addition, increased levels of the chemokine KC/GRO and cytokine interleukin-1β were found. Furthermore, macroglial activation was noted in the inner retina. No alterations in numbers of phagocytic cells, infiltrating macrophages, or vascular pericytes were observed. Post-synaptic density-95 cluster intensity was reduced in the outer nuclear layer, reflecting seizure-induced synaptic changes without disrupted cytoarchitecture in areas with increased microglial activation. The retinal gliosis was decreased by a CX3CR1 immune modulation known to reduce gliosis within epileptic foci, suggesting a common immunological reaction. Conclusions: Our results are the first evidence that epileptic seizures induce an immune response in the retina. It has a potential to become a novel non-invasive tool for detecting brain inflammation through the eyes.
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| 8. |
- Ahl, Matilda, et al.
(author)
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Inflammatory reaction in the retina after focal non-convulsive status epilepticus in mice investigated with high resolution magnetic resonance and diffusion tensor imaging
- 2021
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In: Epilepsy Research. - : Elsevier. - 0920-1211 .- 1872-6844. ; 176
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Journal article (peer-reviewed)abstract
- Pathophysiological consequences of focal non-convulsive status epilepticus (fNCSE) have been difficult to demonstrate in humans. In rats fNCSE pathology has been identified in the eyes. Here we evaluated the use of high-resolution 7 T structural T1-weighted magnetic resonance imaging (MRI) and 9.4 T diffusion tensor imaging (DTI) for detecting hippocampal fNCSE-induced retinal pathology ex vivo in mice. Seven weeks post-fNCSE, increased number of Iba1+ microglia were evident in the retina ipsilateral to the hemisphere with fNCSE, and morphologically more activated microglia were found in both ipsi- and contralateral retina compared to non-stimulated control mice. T1-weighted intensity measurements of the contralateral retina showed a minor increase within the outer nuclear and plexiform layers of the lateral retina. T1-weighted measurements were not performed in the ipsilateral retina due to technical difficulties. DTI fractional anisotropy(FA) values were discretely altered in the lateral part of the ipsilateral retina and unaltered in the contralateral retina. No changes were observed in the distal part of the optic nerve. The sensitivity of both imaging techniques for identifying larger retinal alteration was confirmed ex vivo in retinitis pigmentosa mice where a substantial neurodegeneration of the outer retinal layers is evident. With MR imaging a 50 % decrease in DTI FA values and significantly thinner retina in T1-weighted images were detected. We conclude that retinal pathology after fNCSE in mice is subtle and present bilaterally. High-resolution T1-weighted MRI and DTI independently did not detect the entire pathological retinal changes after fNCSE, but the combination of the two techniques indicated minor patchy structural changes.
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| 9. |
- Ahl, Matilda, et al.
(author)
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Physical Activity Reduces Epilepsy Incidence : a Retrospective Cohort Study in Swedish Cross-Country Skiers and an Experimental Study in Seizure-Prone Synapsin II Knockout Mice
- 2019
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In: Sports medicine - open. - : Springer. - 2199-1170 .- 2198-9761. ; 5:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Epilepsy patients commonly exercise less than the general population. Animal studies indicate beneficial effects of physical activity in established epilepsy, while its effect on the development is currently less known.METHODS: Here, we investigated the incidence of epilepsy during 20 years in a cohort of participants from the long-distance Swedish cross-country ski race Vasaloppet (n = 197,685) and compared it to the incidence of non-participating-matched controls included in the Swedish population register (n = 197,684). Individuals diagnosed with diseases such as stroke and epilepsy before entering the race were excluded from both groups. Experimentally, we also determined how physical activity could affect the development of epilepsy in epilepsy-prone synapsin II knockout mice (SynIIKO), with and without free access to a running wheel.RESULTS: We identified up to 40-50% lower incidence of epilepsy in the Vasaloppet participants of all ages before retirement. A lower incidence of epilepsy in Vasaloppet participants was seen regardless of gender, education and occupation level compared to controls. The participants included both elite and recreational skiers, and in a previous survey, they have reported a higher exercise rate than the general Swedish population. Sub-analyses revealed a significantly lower incidence of epilepsy in participants with a faster compared to slower finishing time. Dividing participants according to specified epilepsy diagnoses revealed 40-50% decrease in focal and unspecified epilepsy, respectively, but no differences in generalized epilepsy. Voluntary exercise in seizure-prone SynIIKO mice for 1 month before predicted epilepsy development decreased seizure manifestation from > 70 to 40%. Brain tissue analyses following 1 month of exercise showed increased hippocampal neurogenesis (DCX-positive cells), while microglial (Iba1) and astrocytic activation (GFAP), neuronal Map2, brain-derived neurotrophic factor and its receptor tyrosine receptor kinase B intensity were unaltered. Continued exercise for additionally 2 months after predicted seizure onset in SynIIKO mice resulted in a 5-fold reduction in seizure manifestation (from 90 to 20%), while 2 months of exercise initiated at the time of predicted seizure development gave no seizure relief, suggesting exercise-induced anti-epileptogenic rather than anti-convulsive effect.CONCLUSION: The clinical study and the experimental findings in mice indicate that physical activity may prevent or delay the development of epilepsy.
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| 12. |
- Avdic, Una, et al.
(author)
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Immune profile in blood following non-convulsive epileptic seizures in rats
- 2019
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In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 10:JUL
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Journal article (peer-reviewed)abstract
- Non-convulsive status epilepticus (NCSE) is a prolonged epileptic seizure with subtle symptoms that may delay clinical diagnosis. Emerging experimental evidence shows brain pathology and epilepsy development following NCSE. New diagnostic/prognostic tools are therefore needed for earlier and better stratification of treatment. Here we examined whether NCSE initiates a peripheral immune response in blood serum from rats that experienced electrically-induced NCSE. ELISA analysis showed an acute transient increase in serum protein levels including interleukin-6 6 h post-NCSE, similar to the immune reaction in the brain. At 4 weeks post-NCSE, when 75% of rats subjected to NCSE had also developed spontaneous seizures, several immune proteins were altered. In particular, markers associated with microglia, macrophages and antigen presenting cells, such as CD68, MHCII, and galectin-3, were increased and the T-cell marker CD4 was decreased in serum compared to both non-stimulated controls and NCSE rats without spontaneous seizures, without correlation to interictal epileptiform activity. Analyses of serum following intracerebral injection of lipopolysaccharide (LPS) showed an acute increase in interleukin-6, but at 4 weeks unaltered levels of MHCII and galectin-3, an increase in CD8 and CD11b and a decrease in CD68. None of the increased serum protein levels after NCSE or LPS could be confirmed in spleen tissue. Our data identifies the possibility to detect peripheral changes in serum protein levels following NCSE, which may be related to the development of subsequent spontaneous seizures.
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| 13. |
- Avdic, Una, et al.
(author)
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Levetiracetam and N-Cadherin Antibody Alleviate Brain Pathology Without Reducing Early Epilepsy Development After Focal Non-convulsive Status Epilepticus in Rats
- 2021
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In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 12
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Journal article (peer-reviewed)abstract
- Focal non-convulsive status epilepticus (fNCSE) is a neurological condition characterized by a prolonged seizure that may lead to the development of epilepsy. Emerging experimental evidence implicates neuronal death, microglial activation and alterations in the excitatory and inhibitory synaptic balance as key features in the pathophysiology following fNCSE. We have previously reported alterations in the excitatory adhesion molecule N-cadherin in rats with fNCSE originating from the hippocampus that subsequently also develop spontaneous seizures. In this study, fNCSE rats were treated intraperitoneally with the conventional anti-epileptic drug levetiracetam in combination with intraparenchymal infusion of N-cadherin antibodies (Ab) for 4 weeks post-fNCSE. The N-cadherin Ab was infused into the fornix and immunohistochemically N-cadherin Ab-stained neurons were detected within the dorsal hippocampal structures as well as in superjacent somatosensory cortex. Continuous levetiracetam treatment for 4 weeks post-fNCSE reduced microglia activation, including cell numbers and morphological changes, partly decreased neuronal cell loss, and excitatory post-synaptic scaffold protein PSD-95 expression in selective hippocampal structures. The additional treatment with N-cadherin Ab did not reverse neuronal loss, but moderately reduced microglial activation, and further reduced PSD-95 levels in the dentate hilus of the hippocampus. Despite the effects on brain pathology within the epileptic focus, neither monotherapy with systemic levetiracetam nor levetiracetam in combination with local N-cadherin Ab administration, reduced the amount of focal or focal evolving into bilateral convulsive seizures, seizure duration, or interictal epileptiform activity during 1 month of continuous electroenephalogram recordings within the hippocampus after fNCSE. Behavioral tests for spatial memory, anxiety, social interaction and anhedonia did not detect gross behavioral differences between fNCSE rats with or without treatment. The results reveal the refractory features of the present rodent model of temporal lobe epilepsy following fNCSE, which supports its clinical value for further therapeutic studies. We identify the persistent development of epilepsy following fNCSE, in spite of partly reduced brain pathology within the epileptic focus.
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| 14. |
- Avdic, Una, et al.
(author)
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Nonconvulsive status epilepticus in rats leads to brain pathology
- 2018
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In: Epilepsia. - : Wiley. - 0013-9580 .- 1528-1167. ; 59:5, s. 945-958
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Journal article (peer-reviewed)abstract
- Objective: Status epilepticus (SE) is an abnormally prolonged epileptic seizure that if associated with convulsive motor symptoms is potentially life threatening for a patient. However, 20%-40% of patients with SE lack convulsive events and instead present with more subtle semiology such as altered consciousness and less motor activity. Today, there is no general consensus regarding to what extent nonconvulsive SE (NCSE) is harmful to the brain, which adds uncertainty to stringent treatment regimes. Methods: Here, we evaluated brain pathology in an experimental rat and mouse model of complex partial NCSE originating in the temporal lobes with Western blot analysis, immunohistochemistry, and ex vivo diffusion tensor imaging (DTI). The NCSE was induced by electrical stimulation with intrahippocampal electrodes and terminated with pentobarbital anesthesia. Video-electroencephalographic recordings were performed throughout the experiment. Results: DTI of mice 7 weeks post-NCSE showed no robust long-lasting changes in fractional anisotropy within the hippocampal epileptic focus. Instead, we found pathophysiological changes developing over time when measuring protein levels and cell counts in extracted brain tissue. At 6 and 24 hours post-NCSE in rats, few changes were observed within the hippocampus and cortical or subcortical structures in Western blot analyses of key components of the cellular immune response and synaptic protein expression, while neurodegeneration had started. However, 1 week post-NCSE, both excitatory and inhibitory synaptic protein levels were decreased in hippocampus, concomitant with an excessive microglial and astrocytic activation. At 4 weeks, a continuous immune response in the hippocampus was accompanied with neuronal loss. Levels of the excitatory synaptic adhesion molecule N-cadherin were decreased specifically in rats that developed unprovoked spontaneous seizures (epileptogenesis) within 1 month following NCSE, compared to rats only exhibiting acute symptomatic seizures within 1 week post-NCSE. Significance: These findings provide evidence for a significant brain pathology following NCSE in an experimental rodent model.
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| 15. |
- Bagni, T., et al.
(author)
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Modeling Results of the Quench Behavior of a Nb-Ti Canted-Cosine-Theta Corrector Magnet for LHC
- 2024
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In: IEEE transactions on applied superconductivity (Print). - : IEEE. - 1051-8223 .- 1558-2515. ; 34:5
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Journal article (peer-reviewed)abstract
- A newly designed superconducting magnet of the Canted-Cosine-Theta (CCT) type was developed as a result of a collaboration between Swedish universities (Uppsala and Linneaus) and Swedish industries. This magnet was designed to function as a replacement of the present LHC orbit corrector magnets, which are approaching their end of life due to the radiation load. As a result, the new CCT magnet was developed to be more radiation tolerant and to constitute a one-to-one replacement to the currently installed version, which is a 1 m long 70 mm double aperture dipole magnet. The final magnet, which is currently under construction, will be tested at FREIA laboratory at Uppsala University and generate a magnetic field of 3.3 T and an integrated field of 2.8 Tm at about 85 A. To examine the magnet quench behavior and to identify a suitable quench protection system, the 3D electro-magnetic and thermal behavior of the coil was modeled using the RAT-Raccoon software. Based on the simulation results, a Metrosil varistor was selected to protect the magnet during the test. In this article, we report the results of the numerical analysis. The magnet model is equipped with a spot heater to initialize the quench and the temperature and voltages are monitored during the avalanche effect. The simulated current decay and the hot-spot temperature are analyzed with a focus on the impact of quench-back on the magnet protection.
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| 16. |
- Bass, Gary Alan, 1979-, et al.
(author)
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Techniques for mesoappendix transection and appendix resection: insights from the ESTES SnapAppy study
- 2023
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In: European Journal of Trauma and Emergency Surgery. - : Springer Science and Business Media LLC. - 1863-9933 .- 1615-3146 .- 1863-9941. ; 49, s. 17-32
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Journal article (peer-reviewed)abstract
- Introduction: Surgically managed appendicitis exhibits great heterogeneity in techniques for mesoappendix transection and appendix amputation from its base. It is unclear whether a particular surgical technique provides outcome benefit or reduces complications. Material and methods: We undertook a pre-specified subgroup analysis of all patients who underwent laparoscopic appendectomy at index admission during SnapAppy (ClinicalTrials.gov Registration: NCT04365491). We collected routine, anonymized observational data regarding surgical technique, patient demographics and indices of disease severity, without change to clinical care pathway or usual surgeon preference. Outcome measures of interest were the incidence of complications, unplanned reoperation, readmission, admission to the ICU, death, hospital length of stay, and procedure duration. We used Poisson regression models with robust standard errors to calculate incident rate ratios (IRRs) and 95% confidence intervals (CIs). Results: Three-thousand seven hundred sixty-eight consecutive adult patients, included from 71 centers in 14 countries, were followed up from date of admission for 90days. The mesoappendix was divided hemostatically using electrocautery in 1564(69.4%) and an energy device in 688(30.5%). The appendix was amputated by division of its base between looped ligatures in 1379(37.0%), with a stapler in 1421(38.1%) and between clips in 929(24.9%). The technique for securely dividing the appendix at its base in acutely inflamed (AAST Grade 1) appendicitis was equally divided between division between looped ligatures, clips and stapled transection. However, the technique used differed in complicated appendicitis (AAST Grade 2 +) compared with uncomplicated (Grade 1), with a shift toward transection of the appendix base by stapler (58% vs. 38%; p < 0.001). While no statistical difference in outcomes could be detected between different techniques for division of appendix base, decreased risk of any [adjusted IRR (95% CI): 0.58 (0.41–0.82), p = 0.002] and severe [adjusted IRR (95% CI): 0.33 (0.11–0.96), p = 0.045] complications could be detected when using energy devices. Conclusions: Safe mesoappendix transection and appendix resection are accomplished using heterogeneous techniques. Technique selection for both mesoappendix transection and appendix resection correlates with AAST grade. Higher grade led to more ultrasonic tissue transection and stapled appendix resection. Higher AAST appendicitis grade also correlated with infection-related complication occurrence. Despite the overall well-tolerated heterogeneity of approaches to acute appendicitis, increasing disease acuity or complexity appears to encourage homogeneity of intraoperative surgical technique toward advanced adjuncts.
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| 18. |
- Bäckström, Filip, et al.
(author)
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Reduced epilepsy development in synapsin 2 knockout mice with autistic behavior following early systemic treatment with interleukin-6 receptor antibody
- 2023
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In: Epilepsy Research. - : Elsevier BV. - 1872-6844 .- 0920-1211. ; 191
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Journal article (peer-reviewed)abstract
- BACKGROUND: Individuals with autism spectrum disorder (ASD) have an increased risk of developing epilepsy. Both ASD and epilepsy have been associated with increased levels of immune factors in the blood, including the proinflammatory cytokine interleukin 6 (IL-6). Mice lacking the synapsin 2 gene (Syn2 KO) exhibit ASD-like behavior and develop epileptic seizures. Their brains display neuroinflammatory changes including elevated IL-6 levels. We aimed to investigate the effect of systemic IL-6 receptor antibody (IL-6R ab) treatment on seizure development and frequency in Syn2 KO mice.MATERIAL AND METHODS: Weekly systemic (i.p.) injections of IL-6R ab or saline were given to Syn2 KO mice starting either early in life at 1 month of age, before seizure debut or at 3 months of age, directly after seizure debut and continued for 4 or 2 months, respectively. Seizures were provoked by handling the mice three times per week. The neuroinflammatory response and synaptic protein levels in the brain were determined by ELISA, immunohistochemistry and western blots. In an additional group of Syn2 KO mice, with IL-6R ab treatment early in life, ASD-related behavioral tests including social interaction and repetitive self-grooming, as well as cognitive memory and depressive-/anxiety-like tests, and actigraphy measurements of circadian sleep-awake rhythm were analyzed.RESULTS: The IL-6R ab treatment reduced seizure development and frequency in Syn2 KO mice when initiated before, but not after, seizure debut. However, early treatment did not reverse the neuroinflammatory response or the imbalance in synaptic protein levels in the brain previously reported in Syn2 KO mice. The treatment did not affect social interaction, performance in memory, depressive-/anxiety-like tests or the sleep-awake rhythm of Syn2 KO mice.CONCLUSION: These findings suggest the involvement of IL-6 receptor signaling during epilepsy development in Syn2 KO mice, without significant alterations of the immune reaction in the brain, and independently of cognitive performance, mood and circadian sleep-awake rhythm.
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| 19. |
- Forssten, Maximilian Peter, 1996-, et al.
(author)
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Surgical management of acute appendicitis during the European COVID-19 second wave: safe and effective
- 2023
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In: European Journal of Trauma and Emergency Surgery. - : Springer Science and Business Media LLC. - 1863-9933 .- 1615-3146 .- 1863-9941. ; 49, s. 57-67
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Journal article (peer-reviewed)abstract
- Introduction: The COVID-19 (SARS-CoV-2) pandemic drove acute care surgeons to pivot from long established practice patterns. Early safety concerns regarding increased postoperative complication risk in those with active COVID infection promoted antibiotic-driven non-operative therapy for select conditions ahead of an evidence-base. Our study assesses whether active or recent SARS-CoV-2 positivity increases hospital length of stay (LOS) or postoperative complications following appendectomy. Methods: Data were derived from the prospective multi-institutional observational SnapAppy cohort study. This preplanned data analysis assessed consecutive patients aged ≥ 15years who underwent appendectomy for appendicitis (November 2020–May 2021). Patients were categorized based on SARS-CoV-2 seropositivity: no infection, active infection, and prior infection. Appendectomy method, LOS, and complications were abstracted. The association between SARS-CoV-2 seropositivity and complications was determined using Poisson regression, while the association with LOS was calculated using a quantile regression model. Results: Appendectomy for acute appendicitis was performed in 4047 patients during the second and third European COVID waves. The majority were SARS-CoV-2 uninfected (3861, 95.4%), while 70 (1.7%) were acutely SARS-CoV-2 positive, and 116 (2.8%) reported prior SARS-CoV-2 infection. After confounder adjustment, there was no statistically significant association between SARS-CoV-2 seropositivity and LOS, any complication, or severe complications. Conclusion: During sequential SARS-CoV-2 infection waves, neither active nor prior SARS-CoV-2 infection was associated with prolonged hospital LOS or postoperative complication. Despite early concerns regarding postoperative safety and outcome during active SARS-CoV-2 infection, no such association was noted for those with appendicitis who underwent operative management.
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| 23. |
- Henriques, Thomas, et al.
(author)
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Letter to the editor
- 2001
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In: Spine. - 0362-2436 .- 1528-1159. ; 26:21, s. 2405-
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Journal article (pop. science, debate, etc.)
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